Inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

This application claims priority to provisional application 60/014,592,filed Apr. 3, 1996, and provisional application 60/022,332, filed Jul.24, 1996

BACKGROUND OF THE INVENTION

The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) are part of asignalling pathway that links cell surface growth factor receptors tonuclear signals initiating cellular proliferation. Biological andbiochemical studies of Ras action indicate that Ras functions like aG-regulatory protein. In the inactive state, Ras is bound to GDP. Upongrowth factor receptor activation Ras is induced to exchange GDP for GTPand undergoes a conformational change. The GTP-bound form of Raspropagates the growth stimulatory signal until the signal is terminatedby the intrinsic GTPase activity of Ras, which returns the protein toits inactive GDP bound form (D. R. Lowy and D. M. Willumsen, Ann. Rev.Biochem. 62:851-891 (1993)). Mutated ras genes (Ha-ras, Ki4a-ras,Ki4b-ras and N-ras) are found in many human cancers, includingcolorectal carcinoma, exocrine pancreatic carcinoma, and myeloidleukemias. The protein products of these genes are defective in theirGTPase activity and constitutively transmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys Cell, 62:81-88 (1990);Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al.,Science, 249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin four general classes (S. Graham, Expert Opinion Ther. Patents, (1995)5:1269-1285). The first are analogs of farnesyl diphosphate (FPP), whilea second class of inhibitors is related to the protein substrates (e.g.,Ras) for the enzyme. Bisubstrate inhibitors and inhibitors offarnesyl-protein transferase that are non-competitive with thesubstrates have also been described. The peptide derived inhibitors thathave been described are generally cysteine containing molecules that arerelated to the CAAX motif that is the signal for protein prenylation.(Schaber et al., ibid; Reiss et. al., ibid; Reiss et al., PNAS,88:732-736 (1991)). Such inhibitors may inhibit protein prenylationwhile serving as alternate substrates for the farnesyl-proteintransferase enzyme, or may be purely competitive inhibitors (U.S. Pat.No. 5,141,851, University of Texas; N. E. Kohl et al., Science,260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)). Ingeneral, deletion of the thiol from a CAAX derivative has been shown todramatically reduce the inhibitory potency of the compound. However, thethiol group potentially places limitations on the therapeuticapplication of FPTase inhibitors with respect to pharmacokinetics,pharmacodynamics and toxicity. Therefore, a functional replacement forthe thiol is desirable.

It has recently been disclosed that certain tricyclic compounds whichoptionally incorporate a piperidine moiety are inhibitors of FPTase (WO95/10514, WO 95/10515 and WO 95/10516). Imidazole-containing inhibitorsof farnesyl protein transferase have also been disclosed (WO 95/09001and EP 0 675 112 Al).

It has recently been reported that farnesyl-protein transferaseinhibitors are inhibitors of proliferation of vascular smooth musclecells and are therefore useful in the prevention and therapy ofarteriosclerosis and diabetic disturbance of blood vessels (JPH7-112930).

It is, therefore, an object of this invention to develop low molecularweight compounds that will inhibit farnesyl-protein transferase andthus, the post-translational farnesylation of proteins. It is a furtherobject of this invention to develop chemotherapeutic compositionscontaining the compounds of this invention and methods for producing thecompounds of this invention.

SUMMARY OF THE INVENTION

The present invention comprises peptidomimetic arylheteroaryl-containingcompounds which inhibit the farnesyl-protein transferase. Furthercontained in this invention are chemotherapeutic compositions containingthese farnesyl transferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formula A:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition offarnesyl-protein transferase and the farnesylation of the oncogeneprotein Ras. In a first embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula A: ##STR2##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, R¹¹ C(O)O--, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--,R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰--;

R², R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubsfituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R², R³, R⁴ or R⁵ is unsubstituted or substitutedheterocycle, attachment of R², R³, R⁴ or R⁵ to the phenyl ring isthrough a substitutable heterocycle ring carbon;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹¹ C(O)O--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO, ##STR3## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, cyanophenyl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ C(O)NH--;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, halogen, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle;

X is a bond, --CH═CH--, O, --C(═O)--, --C(O)NR⁷ --, --NR⁷ C(O)--,--C(O)O--, --OC(O)--, --C(O)NR⁷ C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰),--N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is independently 0, 1, 2, 3 or 4;

q is 0, 1, 2 or 3;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention is illustratedby the following formula: ##STR4## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R², R³, R⁴ and R⁵ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(o)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R², R³, R⁴ or R⁵ is unsubstituted or substitutedheterocycle, attachment of R², R³, R⁴ or R⁵ to the phenyl ring isthrough a substitutable heterocycle ring carbon;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ ;

R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted orsubstituted with:

a) C₁₋₄ alkoxy,

b) aryl or heterocycle,

c) halogen,

d) HO, ##STR5## f) --SO₂ R¹¹ g) N(R¹⁰)₂ or

h) C₁₋₄ perfluoroalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R⁹ is independently selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹¹O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, CN,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl;

X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷ C(O)--, --NR⁷--, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

q is independently 0, 1, 2 or 3;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen; and

t is 0 or 1;

or the pharmaceutically acceptable salts thereof.

A preferred embodiment of the compounds of this invention areillustrated by the formula B: ##STR6## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ ;

provided that when R² or R³ is unsubstituted or substituted heterocycle,attachment of R² or R³ to the phenyl ring is through a substitutableheterocycle ring carbon;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O --, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, orS(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyl,triazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0,1, 2, 3 or 4; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

Another preferred embodiment of the compounds of this invention areillustrated by the formula C: ##STR7## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰O--, --N(R¹⁰)₂, F or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) unsubstituted or substituted C₁ -C₆ alkyl wherein the substituent onthe substituted C₁ -C₆ alkyl is selected from unsubstituted orsubstituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰O-- and --N(R¹⁰)₂ ;

R² and R³ are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R² or R³ is unsubstituted or substituted heterocycle,attachment of R² or R³ to the phenyl ring is through a substitutableheterocycle ring carbon;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, substituted heterocycle C₁ -C₆alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, C₁ -C₆ alkyl,trifluoromethyl and halogen;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl, benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, isoquinolinyltriazolyl and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ;

provided that when V is heterocycle, attachment of V to R⁸ and to A¹ isthrough a substitutable ring carbon;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--;

m is 0, 1 or 2;

n is independently 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰--, --NR¹⁰ or O; and

r is 0 to 5, provided that r is 0 when V is hydrogen;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula D: ##STR8##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl orC₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R² is unsubstituted or substituted heterocycle,attachment of R² to the phenyl ring is through a substitutableheterocycle ring carbon;

R³ is selected from H, halogen, C₁ -C₆ alkyl and CF₃ ;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂ or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)-- or S(O)_(m) ;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --N(R¹⁰)--, O or--C(═O)--;

n is 0 or 1; provided that n is not 0 if A¹ is a bond, O, --N(R¹⁰)--, orS(O)_(m) ;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In another more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula E:##STR9## wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F,C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂-C₆ alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹ OC(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R² is unsubstituted or substituted heterocycle,attachment of R² to the phenyl ring is through a substitutableheterocycle ring carbon;

R³ is selected from H, halogen, C₁ -C₆ alkyl and CF_(3;)

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --;

provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --N(R¹⁰)--, O or--C(═O)--;

n is 0 or 1;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula F: ##STR10##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, C₃ -C₁₀ cycloalkyl orC₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ --, --N(R¹⁰)₂ or F,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ ;

provided that when R² is unsubstituted or substituted heterocycle,attachment of R² to the phenyl ring is through a substitutableheterocycle ring carbon;

R³ is selected from H, halogen, CH₃ and CF_(3;)

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --N(R¹⁰)--, O or--C(═O)--;

m is 0, 1 or 2; and

p is 0, 1, 2, 3 or 4;

or the pharmaceutically acceptable salts thereof.

In a further embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula G: ##STR11##wherein: a is N or C;

from 0-4 of b, c, d and e are independently N, NH, O and S, and theremaining b, c, d and e atoms are independently CH, provided that if ais C, then at least one of b, c, d or e is independently N, NH, O or S;

R^(1a) is independently selected from: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F,C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle or C₃ -C₁₀ cycloalkyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R² is selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

provided that when R² is unsubstituted or substituted heterocycle,attachment of R² to the phenyl ring is through a substitutableheterocycle ring carbon;

R³ is selected from H, halogen. CH₃ and CF₃ ;

R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:

a) hydrogen,

b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --;

R^(9a) and R^(9b) are independently hydrogen, halogen, CF₃ or methyl;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is independently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆substituted heteroaralkyl, aryl, substituted aryl, heteroaryl,substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and2,2,2-trifluoroethyl;

A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ;

m is 0, 1 or 2; and

n is 0 or 1;

or the pharmaceutically acceptable salts thereof.

Specific examples of the compounds of the invention are: ##STR12## orthe pharmaceutically acceptable salts thereof.

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. When any variable (e.g. aryl, heterocycle,R^(1a), R^(1b) etc.) occurs more than one time in any constituent, itsdefinition on each occurence is independent at every other occurence.Also, combinations of substituents/or variables are permissible only ifsuch combinations result in stable compounds.

As used herein, "alkyl" and the alkyl portion of aralkyl and similarterms, is intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms; "alkoxy" represents an alkyl group of indicated number of carbonatoms attached through an oxygen bridge.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

"Alkynyl" groups include those groups having the specified number ofcarbon atoms and having one triple bonds. Examples of alkynyl groupsinclude acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and the like.

"Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

As used herein, "aryl," and the aryl portion of aralkyl and aroyl, isintended to mean any stable monocyclic or bicyclic carbon ring of up to7 members in each ring, wherein at least one ring is aromatic. Examplesof such aryl elements include phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicheterocyclic ring which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to four heteroatoms selected fromthe group consisting of N, O, and S, and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The heterocyclic ring may be attached at any heteroatom or carbonatom which results in the creation of a stable structure. Examples ofsuch heterocyclic elements include, but are not limited to, azepinyl,benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopyrrolidinyl, pyridyl,pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,thienofuryl, thienothienyl, and thienyl.

As used herein, "heteroaryl" is intended to mean any stable monocyclicor bicyclic carbon ring of up to 7 members in each ring, wherein atleast one ring is aromatic and wherein from one to four carbon atoms arereplaced by heteroatoms selected from the group consisting of N, O, andS. Examples of such heterocyclic elements include, but are not limitedto, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl,benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, furyl, imidazolyl, indolinyl, indolyl, isochromanyl,isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl,pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl,quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, thiazolyl, thienofuryl, thienothienyl, andthienyl.

As used herein in the definition of R⁷, the substituted C₁₋₈ alkyl,substituted C₃₋₆ cycloalkyl, substituted aroyl, substituted aryl,substituted heteroaroyl, substituted arylsulfonyl, substitutedheteroarylsulfonyl and substituted heterocycle include moietiescontaining from 1 to 3 substituent s in addition to the point ofattachment to the rest of the compound.

As used herein, when no specific substituents are set forth, the terms"substituted aryl", "substituted heterocycle" and "substitutedcycloalkyl" are intended to include the cyclic group which issubstituted on a substitutable ring carbon atom with 1 or 2substitutents selected from the group which includes but is not limitedto F, Cl, Br, CF₃, NH₂, N(C₁ -C₆ alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--,--OH, (C₁ -C₆ alkyl)S(O)_(m) --, (C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--,(C₁ -C₆ alkyl)C(O)--, (C₁ -C₆ alkyl)OC(O)--, N₃, (C₁ -C₆alkyl)OC(O)NH--, phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, thienyl, furyl, isothiazolyl and C₁ -C₂₀ alkyl.

Lines drawn into the ring systems from substituents (such as from R²,R³, R⁴ etc.) indicate that the indicated bond may be attached to any ofthe substitutable ring carbon atoms.

The moiety designated by the following structure ##STR13## represents anaromatic 5-membered heterocyclic ring and includes the following ringsystems: ##STR14## Preferably the aromatic 5-membered heterocyclic ringis selected from: ##STR15##

Preferably, R^(1a) and R^(1b) are independently selected from: hydrogen,R¹¹ C(O)O--, --N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ --, R¹⁰ O-- or unsubstituted orsubstituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted phenyl,--N(R¹⁰)₂, R¹⁰ O-- and R¹⁰ C(O)NR¹⁰ --.

Preferably, R² is selected from:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, CN, NO₂,R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl,

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --.

Preferably, R³ is selected from: hydrogen, halogen, trifluoromethyl,trifluoromethoxy and C₁ -C₆ alkyl.

Preferably, R⁴ and R⁵ are hydrogen.

Preferably, R^(6a), R^(6b), R^(6c) and R^(6d) are independently selectedfrom:

a) hydrogen,

b) C₃ -C₁₀ cycloalkyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹S(O)_(m) --, CN, NO₂, R¹⁰ C(O)-- or --N(R¹⁰)₂,

c) unsubstituted C₁ -C₆ alkyl;

d) substituted C₁ -C₆ alkyl wherein the substituent on the substitutedC₁ -C₆ alkyl is selected from unsubstituted or substituted aryl, C₃ -C₁₀cycloalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)-- or --N(R¹⁰)₂.

Preferably, R⁸ is independently selected from:

a) hydrogen, and

b) aryl, substituted aryl, heterocycle, substituted heterocycle, C₁ -C₆perfluoroalkyl or CN.

Preferably, R⁹ is hydrogen, halogen, CF₃ or methyl.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A²¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl. Morepreferably, V is phenyl.

Preferably, W is selected from imidazolinyl, imidazolyl, oxazolyl,pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More preferably, W isselected from imidazolyl and pyridyl.

Preferably, n and r are independently 0, 1, or 2.

Preferably s is 0.

Preferably t is 1.

Preferably, the moiety ##STR16## is selected from: ##STR17##

It is intended that the definition of any substituent or variable (e.g.,R^(1a), R^(1b), R⁹, n, etc.) at a particular location in a molecule beindependent of its definitions elsewhere in that molecule. Thus,--N(R¹⁰)₂ represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understoodthat substituents and substitution patterns on the compounds of theinstant invention can be selected by one of ordinary skill in the art toprovide compounds that are chemically stable and that can be synthesizedby techniques known in the art, as well as those methods set forthbelow, from readily available starting materials.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Schemes 1-22, in addition toother standard manipulations such as ester hydrolysis, cleavage ofprotecting groups, etc., as may be known in the literature orexemplified in the experimental procedures. Substituents R², R⁶ and R⁸,as shown in the Schemes, represent the substituents R², R³, R⁴, R⁵,R^(6a), R^(6b), R^(6c), R^(6d) and R⁸ ; although only one such R², R⁶ orR⁸ is present in the intermediates and products of the schemes, it isunderstood that the reactions shown are also applicable when such arylor heteroaryl moieties contain multiple substituents.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Schemes. Other reactions useful in the preparation of heteroarylmoieties are described in "Comprehensive Organic Chemistry, Volume 4:Heterocyclic Compounds" ed. P. G. Sammes, Oxford (1979) and referencestherein. Aryl-aryl coupling is generally described in "ComprehensiveOrganic Functional Group Transformations," Katritsky et al. eds., pp472-473, Pergamon Press (1995).

Synopsis of Schemes 1-22:

The requisite intermediates are in some cases commercially available, orcan be prepared according to literature procedures, for the most part.Schemes 1-13 illustrate synthesis of the instant arylheteroaryl compoundwhich incorporate a preferred benzylimidazolyl sidechain. Thus, inScheme 1, for example, a arylheteroaryl intermediate that is notcommercially available may be synthesized by methods known in the art.Thus, a suitably substituted heteroaryl boronic acid, such as a suitablysubstituted thienyl boronic acid 1 may be reacted under Suzuki couplingconditions (Pure Appl. Chem., 63:419 (1991)) with a suitably substitutedhalogenated benzoic acid, such as 4-iodobenzoic acid, to provide thearylheteroaryl carboxylic acid II. The acid may be reduced and thetriflate of the intermediate alcohol III may be formed in situ andcoupled to a suitably substituted benzylimidazolyl IV to provide, afterdeprotection, the instant compound V.

Schemes 2-5 illustrate other methods of synthesizing the key alcoholintermediates, which can then be processed as described in Scheme 1.Thus, Scheme 2 illustrates the analogous series of arylheteroarylalcohol forming reactions starting with the halogenated arylaldehyde.

Scheme 3 illustrates the reaction wherein the "terminal" 5-memberedheteroaryl moiety is employed in the Suzuki coupling as the halogenatedreactant. Such a coupling reaction is also compatible when one of thereactants incorporates a suitably protected hydroxyl functionality asillustrated in Scheme 4.

Negishi chemistry (Org. Synth., 66:67 (1988)) may also be employed toform the arylheteroaryl component of the instant compounds, as shown inScheme 5. Thus, a suitably substituted zinc bromide adduct may becoupled to a suitably substituted phenyl halide in the presence ofnickel (II) to provide the arylheteroaryl VII. The heteroaryl halide andthe zinc bromide adduct may be selected based on the availability of thestarting reagents.

Scheme 6 illustrates the utilization of a suitably substitutedarylheteroarylmethyl bromide in the reaction with the protectedimidazole as described in Scheme 1.

As illustrated in Scheme 7, the sequence of coupling reactions may bemodified such that the phenyl-heteroaryl bond is formed last. Thus, asuitably substituted imidazole may first be alkylated with a suitablysubstituted benzyl halide to provide intermediate VIII. IntermediateVIII can then undergo Suzuki type coupling to a suitably substitutedheteroaryl boronic acid.

Scheme 8 illustrates synthesis of an instant compound wherein anon-hydrogen R^(9b) is incorporated in the preferred W moiety,imidazolyl. Thus, a readily available 4-substituted imidazole IX may beselectively iodinated to provide the 5-iodoimidazole X. That imidazolemay then be protected and coupled to a suitably substituted benzylmoiety to provide intermediate XI. Intermediate XI can then undergo thealkylation reactions that were described hereinabove.

Scheme 9 illustrates synthesis of instant compounds that incorporate apreferred imidazolyl moiety connected to the arylheteroaryl via an alkylamino, sulfonamide or amide linker. Thus, the 4-aminoalkylimidazole XII,wherein the primary amine is protected as the phthalimide, isselectively alkylated then deprotected to provide the amine XIII. Theamine XIII may then react under conditions well known in the art withvarious activated arylheteroaryl moieties to provide the instantcompounds shown.

Compounds of the instant invention wherein the A¹ (CR^(1a) ₂)_(n) A²(CR^(1a) ₂)_(n) linker is oxygen may be synthesized by methods known inthe art, for example as shown in Scheme 10. The suitably substitutedphenol XIV may be reacted with methyl N-(cyano)methanimidate to providethe 4-phenoxyimidazole XV. After selective protection of one of theimidazolyl nitrogens, the intermediate XVI can undergo alkylationreactions as described for the benzylimidazoles hereinabove.

Scheme 11 illustrates an analogous series of reactions wherein the(CR^(1b) ₂)_(p) X(CR^(1b) ₂)_(p) linker of the instant compounds isoxygen. Thus, a suitably substituted haloaryl alcohol, such as4-bromophenol and the like, is reacted with methyl N-(cyano)methanimidate to provide intermediate XVI. Intermediate XVI is thenprotected and, if desired to form a compound of a preferred embodiment,alkylated with a suitably protected benzyl. The intermediate XVII canthen be coupled to a heteroaryl moiety by Suzuki chemistry to providethe instant compound.

Compounds of the instant invention wherein the A¹ (CR^(1a) ₂)_(n) A²(CR^(1a) ₂)_(n) linker is a substituted methylene may be synthesized bythe methods shown in Scheme 12. Thus, the N-protected imidazolyl iodideXVIII is reacted, under Grignard conditions with a suitably protectedbenzaldehyde to provide the alcohol XIX. Acylation, followed by thealkylation procedure illustrated in the Schemes above (in particular,Scheme 1) provides the instant compound XX. If other R^(1a) substituents are desired, the acetyl moiety can be manipulated as illustrated inthe Scheme.

Grignard chemistry may also be employed to form a substituted alkyllinker between the arylheteroaryl and the preferred W (imidazolyl) asshown in Scheme 13. Similar substituent manipulation as shown in Scheme12 may be performed on the fully functionalized compound whichincorporates an R^(1b) hydroxyl moiety. ##STR18##

Schemes 14-22 illustrate reactions wherein the moiety ##STR19##incorporated in the compounds of the instant invention is represented byother than a substituted imidazole-containing group.

Thus, the intermediates whose synthesis are illustrated in Schemeshereinabove and other arylheteroaryl intermediates obtained commerciallyor readily synthesized, can be coupled with a variety of aldehydes. Thealdehydes can be prepared by standard procedures, such as that describedby 0. P. Goel, U. Krolls, M. Stier and S. Kesten in Organic Syntheses,1988, 67, 69-75, from the appropriate amino acid. Grignard chemistry maybe utilized, as shown in Scheme 14, to incorporate the arylheteroarylmoiety. Thus, a suitably substituted w arylheteroaryl Grignard reagentis reacted with an aldehyde to provide the C-alkylated instant compoundXXI. Compound XXI can be deoxygenated by methods known in the art, suchas a catalytic hydrogention, then deprotected with trifluoroacetic acidin methylene chloride to give the final compound XXII. The final productXXII may be isolated in the salt form, for example, as atrifluoroacetate, hydrochloride or acetate salt, among others. Theproduct diamine XXII can further be selectively protected to obtainXXIII, which can subsequently be reductively alkylated with a secondaldehyde to obtain XXIV. Removal of the protecting group, and conversionto cyclized products such as the dihydroimidazole XXV can beaccomplished by literature procedures.

If the arylheteroaryl subunit reagent is reacted with an aldehyde whichalso has a protected hydroxyl group, such as XXVI in Scheme 15, theprotecting groups can be subsequently removed to unmask the hydroxylgroup (Schemes 15, 16). The alcohol can be oxidized under standardconditions to e.g. an aldehyde, which can then be reacted with a varietyof organometallic reagents such as Grignard reagents, to obtainsecondary alcohols such as XXX. In addition, the fully deprotected aminoalcohol XXXI can be reductively alkylated (under conditions describedpreviously) with a variety of aldehydes to obtain secondary amines, suchas XXXII (Scheme 16), or tertiary amines.

The Boc protected amino alcohol XXVIII can also be utilized tosynthesize 2-aziridinylmethylarylheteroaryl such as XXXIII (Scheme 17).Treating XXVIII with 1,1'-sulfonyldiimidazole and sodium hydride in asolvent such as dimethylformamide led to the formation of aziridineXXXIII . The aziridine is reacted with a nucleophile, such as a thiol,in the presence of base to yield the ring-opened product XXXIV.

In addition, the arylheteroaryl subunit reagent can be reacted withaldehydes derived from amino acids such as 0-alkylated tyrosines,according to standard procedures, to obtain compounds such as XL, asshown in Scheme 18. When R' is an aryl group, XL can first behydrogenated to unmask the phenol, and the amine group deprotected withacid to produce XLI. Alternatively, the amine protecting group in XL canbe removed, and 0-alkylated phenolic amines such as XLII produced.

Schemes 19-22 illustrate syntheses of suitably substituted aldehydesuseful in the syntheses of the instant compounds wherein the variable Wis present as a pyridyl moiety. Similar synthetic strategies forpreparing alkanols that incorporate other heterocyclic moieties forvariable W are also well known in the art. ##STR20##

The instant compounds are useful as pharmaceutical agents for mammals,especially for humans. These compounds may be administered to patientsfor use in the treatment of cancer. Examples of the type of cancer whichmay be treated with the compounds of this invention include, but are notlimited to, colorectal carcinoma, exocrine pancreatic carcinoma, myeloidleukemias and neurological tumors. Such tumors may arise by mutations inthe ras genes themselves, mutations in the proteins that can regulateRas activity (i.e., neurofibromin (NF-1), neu, scr, ab1, lck, fyn) or byother mechanisms.

The compounds of the instant invention inhibit farnesyl-proteintransferase and the farnesylation of the oncogene protein Ras. Theinstant compounds may also inhibit tumor angiogenesis, thereby affectingthe growth of tumors (J. Rak et al. Cancer Research, 55:4575-4580(1995)). Such anti-angiogenesis properties of the instant compounds mayalso be useful in the treatment of certain forms of blindness related toretinal vascularization.

The compounds of this invention are also useful for inhibiting otherproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, a component of NF-1is a benign proliferative disorder.

The instant compounds may also be useful in the treatment of certainviral infections, in particular in the treatment of hepatitis delta andrelated viruses (J. S. Glenn et al. Science, 256:1331-1333 (1992).

The compounds of the instant invention are also useful in the preventionof restenosis after percutaneous transluminal coronary angioplasty byinhibiting neointimal formation (C. Indolfi et al. Nature medicine,1:541-545(1995).

The instant compounds may also be useful in the treatment and preventionof polycystic kidney disease (D. L. Schaffner et al. American Journal ofPathology, 142:1051-1060 (1993) and B. Cowley, Jr. et al. FASEB Journal,2:A3160 (1988)).

The instant compounds may also be useful for the treatment of fungalinfections.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The compounds of the instant invention may also be co-administered withother well known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated. Forexample, the instant compounds may be useful in combination with knownanti-cancer and cytotoxic agents. Similarly, the instant compounds maybe useful in combination with agents that are effective in the treatmentand prevention of NF-1, restinosis, polycystic kidney disease,infections of hepatitis delta and related viruses and fungal infections.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's blood-stream by local bolus injection.

As used herein, the term "composition" is intended to encompass aproduct comprising the specified ingredients in the specific amounts, aswell as any product which results, directly or indirectly, fromcombination of the specific ingredients in the specified amounts.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 60mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 40 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known iununological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

Example 1 1-(4-(1,2,3-Thiadiazolyl)-phenylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetate salt

Step A: 1-Trityl-4-(4-Cyanobenzyl)-imidazole

To a suspension of activated zinc dust (3.57 g, 54.98 mmol) in THF (50mL)was added dibromoethane (0.315 mL, 3.60 mmol) and the reactionstirred for 45 minutes under argon at 20° C. The suspension was cooledto 0° C. and α-bromo-p-tolunitrile (9.33 g, 47.6 mmol) in THF (100 niL)was added dropwise over a period of 10 minutes. The reaction was thenallowed to stir at 20° C. for 6 hours and bis(triphenylphosphine)NickelII chloride (2.40 g, 3.64 mmol) and 4-iodo-1-tritylimidazole (15.95 g,36.6 mmol, S. V. Ley, et al., J. Org. Chem. 56, 5739 (1991)) was addedin one portion. The resulting mixture was stirred 16 hours at 20° C. andthen quenched by addition of saturated NH₄ Cl solution (100 mL) and themixture stirred for 2 hours. Saturated aq. NaHCO₃ solution was added togive a pH of 8 and the solution was extracted with EtOAc (2×250 mL),dried, (MgSO₄) and the solvent evaporated in vacuo. The residue waschromatographed (Silica gel, 0-20% EtOAc inCH₂ Cl₂) to afford the titlecompound as a white solid.

¹ H NMR (CDCl₃ 400MHz)δ 7.54 (2H, d, J=7.9Hz), 7.38(1H, s), 7.36-7.29(11H, m), 7.15-7.09(6H, m), 6.58(1H, s) and 3.93(2H, s) ppm.

Step B: 1-(4-(1,2,3-Thiadiazolyl)-phenylmethyl)-5-(4-cyanobenzyl)imidazole trifluoroacetate salt

To 1-Trityl-4-(4-Cyanobenzyl)-imidazole (199 mg, 0.468 mmol) inacetonitrile (1 mL) was added 4-(4-bromomethylphenyl)-1,2,3-thiadiazole(122 mg, 0.478 mmol) and the mixture heated at 55° C. for 16 hours. Theresidue was dissolved in methanol (10 mL) and heated at reflux for 30minutes, cooled and evaporated to dryness. The residue was partitionedbetween sat. aq. NaHCO₃ solution and CH₂ Cl₂. The organic layer wasdried, (NaSO₄) and the solvent evaporated in vacuo. The residue waschromatographed (silica gel, 3% methanol in CH₂ Cl₂) and furtherpurified by preparative HPLC, (gradient elution, 95:5 to 5:95%water:acetonitrile containing 0.1% trifluoroacetic acid) to afford thetitle compound.

FAB MS 358(MH+)

¹ H NMR (CD₃ OD 400MHz)δ 9.28(1H, s), 9.08(1H, d, J=1.5Hz), 8.04(2H, d,J=8.4Hz), 7.55(2H, d, J=8.4Hz), 7.44(1H, s), 7.27(2H, d, J=8.4Hz),7.26(2H, d, J=8.4Hz), 5.47(2H, s) and 4.18(2H, s) ppm.

Example 2 1-(4- Thien-3-yl!phenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

Step A: Methyl (4-thien-3-yl)henzoate

A mixture of methyl 4-iodobenzoate(0.451 g, 1.72 mmol), 3-thienylboronicacid (1.56 g, 12.79 mmol), barium hydroxide (0.813 mg, 2.58 mmol), DME(8 mL) and water (1.5 mL) was purged with dry argon.Tetrakis(triphenyl-phosphine) palladium(O) (99.0 mg, 0.086 mmol) wasadded, and the resultant solution was stirred at 80° C. for 4 hours. Thesolvents were evaporated in vacuo, and the residue partitioned betweenEtOAc and water and acidified with 1 M aq. HCl. The aqueous extract wasseparated, and extracted with EtOAc. The organic extracts were combined,washed with sat. aq. NaHCO₃ and 5% aq. Na₂ S₂ O₃, dried, (Na₂ SO₄)filtered and the solvent evaporated in vacuo. The residue was purifiedby chromatography (Silica gel, CH₂ Cl₂) to afford the title compound.

¹ H NMR (CDCl₃ 400MHz)δ 8.06(2H, d, J=8.4Hz), 7.67(2H, d, J=8.4Hz),7.57(1H, dd, J=1.6 and 2.8Hz), 7.45-7.40(2H, m) and 3.93(3H, s) ppm.

Step B: 4-Thien-3-yl-benzyl alcohol

To a solution of methyl (4-thien-3-yl)benzoate (552 g, 1.60 mmol) in THF(5 mL) at 0° C. was added 1.0 M lithium aluminum hydride in diethylether (1.60 mL, 1.60 mmol) over 10 minutes. The reaction was allowed tostir at ambient temperature for 3 hours, cooled to 0° C., and quenchedby dropwise addition of water (0.10 mL), 4 N aq. NaOH (0.10 mL), andwater (0.30 mL). The reaction was filtered through a pad of Celite andthe filtrate evaporated in vacuo. The title compound was obtained as anoil and was used without furthur purification.

¹ H NMR (CDCl₃ 400MHz)δ 7.60(2H, d, J=8.2Hz), 7.46(1H, t, J=2.2Hz),7.44-7.36(3H, m), 7.30-7.23(1H, m), 4.72(2H, d, J=5.9Hz) and 1.63(1H, t,J=5.9Hz) ppm.

Step C: 1-(4- Thien-3-yl!phenylmethyl)-5-(4-cyanobenzyl)imidazolehydrochloride salt

To a solution of 4-thien-3-yl-benzyl alcohol (253 mg, 1.33 mmol) anddiisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at-78° C. was added trifluoromethanesulfonic anhydride (0.224 mL, 1.33mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture wasadded a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg , 1.33mmol) in dichloromethane (5 mL). The mixture was allowed to warm toambient temperature and stirred for 2 hours. The solvent was evaporatedin vacuo. The residue was dissolved in methanol (50 mL), heated atreflux for 1 hour, and the solvent evaporated in vacuo. The residue waspartitioned between dichloromethane and sat. aq. NaHCO₃ solution. Theorganic layer was dried, (Na₂ SO₄) and the solvent evaporated in vacuo.The residue was chromatographed (silica gel, 2% MeOH in CH₂ Cl₂) and theamine was converted to the HCl salt by treatment with 1.0M HCl inaqueous acetonitrile. Evaporation of the solvent in vacuo afforded thetitle compound as a white solid.

Anal. Calcd for C₂₂ H_(17S) N₃ •1.00 HCl•0.40 EtOAc:

C, 66.36; H, 5.00; N, 9.84.

Found: C, 65.97; H, 4.64; N, 9.61.

FAB MS 356(MH⁺)

¹ H NMR (CD₃ OD, 400MHz)δ 9.00(1H, d, J=1.5Hz), 7.70-7.56(4H, m),7.45(1H, dd, J=5.1 and 2.9Hz), 7.43(1H, dd, J=1.5 and 5.2Hz), 7.39(1H,s), 7.27(2H, d, J=8.4Hz), 7.16(2H, d, J=8.4Hz), 5.39(2H, s) and 4.16(2H,s) ppm.

Example 3

In vitro inhibition of ras farnesvl transferase

Assays offarnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM ³ H!-farnesyl diphosphate ( ³ H!-FPP; 740CBq/mmol, New England Nuclear), 650 nMRas-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0 M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach H cell harvestor, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the ³ H!-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention described in the above Examples1-2 were tested for inhibitory activity against human FPTase by theassay described above and were found to have IC₅₀ of <50 μM.

Example 4

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supplemented with 10%regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTF) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1 M NaCl) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 5

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×104 cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase of the formula A: ##STR21## wherein: a is N or C;from 0-4 ofb, c, d and e are independently N, NH, O and S, and the remaining b, c,d and e atoms are independently CH, provided that if a is C, then atleast one of b, c, d or e is independently N, NH, O or S; R^(1a) isindependently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₁ -C₆ alkyl; R^(1b) is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁ O cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R², R³, R⁴ and R⁵ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl; d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹ O--; provided that when R², R³, R⁴ or R⁵ is unsubstitutedor substituted heterocycle, attachment of R², R³, R⁴ or R⁵ to the phenylring is through a substitutable heterocycle ring carbon; R^(6a), R^(6b),R^(6c) and R^(6d) are independently selected from:a) hydrogen, b)unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl; d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R⁷ is selected from: H; C₁₋₄ alkyl, C₃₋₆ cycloalkyl,heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl,unsubstituted or substituted with:a) C₁₋₄ alkoxy, b) aryl orheterocycle, c) halogen, d) HO, ##STR22## f) SO₂ R¹¹ g) N(R¹⁰)₂ or h)C₁₋₄ perfluoroalkyl; R⁸ is independently selected from:a) hydrogen, b)aryl, substituted aryl, heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a substitutable ring carbon; R⁹ is independently selectedfrom:a) hydrogen, b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹¹ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl,2,2,2-trifluoroethyl,benzyl and aryl; R¹¹ is independently selected fromC₁ -C₆ alkyl and aryl; R¹² is independently selected from hydrogen, C₁-C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁ -C₆heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substituted aryl,heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyland 2,2,2-trifluoroethyl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, irnidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a substitutablering carbon; W is a heterocycle selected from imidazolyl, imidazolinyl,pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl orisoquinolinyl; X is a bond, O, --C(═O)--, --CH═CH--, --C(O)NR⁷ --, --NR⁷C(O)--, --NR⁷ --, --S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ -- or --S(═O)_(m) --;m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; q is independently0, 1, 2 or 3; p is 0, 1, 2, 3 or 4; r is 0 to 5, provided that r is 0when V is hydrogen; and t is 1; provided that A¹ (CR^(1a) ₂)_(n) A²(CR^(1a) ₂)_(n) is not a bond and provided that (CR^(1b) ₂)_(p)--X--(CR^(1b) ₂)_(p) is not a bond;or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1 of the formula B:##STR23## wherein: a is N or C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that if a is C, then at least one of b, c, dor e is independently N, NH, O or S; R^(1a) is independently selectedfrom: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₁ -C₆alkyl; R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) unsubstituted or substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁ O cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R² and R³ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; provided that when R² or R³ is unsubstituted orsubstituted heterocycle, attachment of R² or R³ to the phenyl ring isthrough a substitutable heterocycle ring carbon; R^(6a), R^(6b), R^(6c)and R^(6d) are independently selected from:a) hydrogen, b) unsubstitutedor substituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹¹ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon; R^(9a) and R^(9b) are independently hydrogen,C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰ is independently selectedfrom hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl,benzyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; R¹² isindependently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁-C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substitutedheteroaralkyl, aryl, substituted aryl, heteroaryl, substitutedheteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl,indolyl, quinolinyl, isoquinolinyl, triazolyl and thienyl, c) aryl, d)C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with aheteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl, andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif A¹ is a bond, n is 0 and A² is S(O)_(m) ; provided that when V isheterocycle, attachment of V to R⁸ and to A¹ is through a substitutablering carbon; X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--,--NR¹⁰ --, O or --C(═O)--; m is 0, 1 or 2; n is independently 0, 1, 2, 3or 4; p is 0, 1, 2, 3 or 4; and r is 0 to 5, provided that r is 0 when Vis hydrogen; provided that A¹ (CR^(1a) ₂)_(n) A² (CR^(1a) ₂)_(n) is nota bond and provided that (CR^(1b) ₂)_(p) --X is not a bond;or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 2 of the formula C: ##STR24## wherein: a is N or C;from 0-4 of b,c, d and e are independently N, NH, O and S, and the remaining b, c, dand e atoms are independently CH, provided that if a is C, then at leastone of b, c, d or e is independently N, NH, O or S; R^(1a) isindependently selected from: hydrogen, C₃ -C₁₀ cycloalkyl, R¹⁰ O--,--N(R¹⁰)₂, F or C₁ -C₆ alkyl; R^(1b) is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁ O cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂,F or C₂ -C₆ alkenyl, c) unsubstituted or substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, R¹⁰ O-- and --N(R¹⁰)₂ ; R² and R³ are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ peifluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹⁰ C(O)--NR¹⁰ --; provided that when R² or R³ is unsubstituted orsubstituted heterocycle, attachment of R² or R³ to the phenyl ring isthrough a substitutable heterocycle ring carbon; R^(6a), R^(6b), R^(6c)and R^(6d) are independently selected from:a) hydrogen, b) unsubstitutedor substituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN(R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon; R^(9a) and R^(9b) are independently hydrogen,C₁ -C₆ alkyl, trifluoromethyl and halogen; R¹⁰ is independently selectedfrom hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl,benzyl and aryl; R¹¹is independently selected from C₁ -C₆ alkyl and aryl; R¹² isindependently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁-C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substitutedheteroaralkyl, aryl, substituted aryl, heteroaryl, substitutedheteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ; V isselected from:a) hydrogen, b) heterocycle selected from pyrrolidinyl,imidazolyl, imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,quinolinyl, isoquinolinyl triazolyl and thienyl, c) aryl, d) C₁ -C₂₀alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatomselected from O, S, and N, and e) C₂ -C₂₀ alkenyl, and provided that Vis not hydrogen if A¹ is S(O)_(m) and V is not hydrogen if A¹ is a bond,n is 0 and A² is S(O)_(m) ; provided that when V is heterocycle,attachment of V to R⁸ and to A¹ is through a substitutable ring carbon;X is a bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --NR¹⁰ --, O or--C(═O)--; m is 0, 1 or 2; n is independently 0, 1, 2, 3 or 4; p is 0,1, 2, 3 or 4, provided that p is not 0 if X is a bond, --NR¹⁰ --, NR¹⁰or O; and r is 0 to 5, provided that r is 0 when V is hydrogen; providedthat A¹ (CR^(1a) ₂)_(n) A² (CR^(1a) ₂)_(n) is not a bond and providedthat (CR^(1b) ₂)_(p) --X is not a bond;or a pharmaceutically acceptablesalt thereof.
 4. The compound according to claim 1 of the formula D:##STR25## wherein: a is N or C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that if a is C, then at least one of b, c, dor e is independently N, NH, O or S; R^(1a) is independently selectedfrom: hydrogen, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆ alkenyl, c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl,C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R² is selected from:a) hydrogen,b) unsubstituted or substituted aryl, unsubstituted or substitutedheterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl,halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; provided that when R² is unsubstituted orsubstituted heterocycle, attachment of R² to the phenyl ring is througha substitutable heterocycle ring carbon; R³ is selected from H, halogen,C₁ -C₆ alkyl and CF_(3;) R^(6a), R^(6b), R^(6c) and R^(6d) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, substituted heterocycleC₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN,NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹⁰ C(O)NR¹⁰ --, andc) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --; provided that when R⁸ is heterocycle, attachment of R⁸ toV is through a substitutable ring carbon; R^(9a) and R^(9b) areindependently hydrogen, halogen, CF₃ or methyl; R¹⁰ is independentlyselected from hydrogen, C₁ -C₆ alkyl, 2,2,2-trifluoroethyl,benzyl andaryl; R¹¹ is independently selected from C₁ -C₆ alkyl and aryl; R¹² isindependently selected from hydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁-C₆ substituted aralkyl, C₁ -C₆ heteroaralkyl, C₁ -C₆ substitutedheteroaralkyl, aryl, substituted aryl, heteroaryl, substitutedheteraryl, C₁ -C₆ perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;A¹ is selected from: a bond, --C(O)--, O, --N(R¹⁰)-- or S(O)_(m) ; X isa bond, --CH═CH--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --N(R¹⁰)--, O or--C(═O)--; n is 0 or 1; provided that n is not 0 if A¹ is a bond, O,--N(R¹⁰)--, or S(O)_(m) ; m is 0, 1 or 2; and p is 0, 1, 2, 3 or 4;provided that A¹ (CR^(1a) ₂)_(n) is not a bond and provided that(CR^(1b) ₂)_(p) --X is not a bond;or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 3 of the formula E:##STR26## wherein: a is N or C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that if a is C, then at least one of b, c, dor e is independently N, NH, O or S; R^(1a) is independently selectedfrom: hydrogen, R¹⁰ O--, --N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆alkyl; R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂, F or C₂ -C₆alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R² is selected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; provided that when R² is unsubstituted orsubstituted heterocycle, attachment of R² to the phenyl ring is througha substitutable heterocycle ring carbon; R³ is selected from H, halogen,C₁ -C₆ alkyl and CF_(3;) R^(6a), R^(6b), R^(6c) and R^(6d) areindependently selected from:a) hydrogen, b) unsubstituted or substitutedaryl, unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹ O)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--,CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c)unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein thesubstituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹ O--; R⁸is independently selected from:a) hydrogen, b) aryl, substituted aryl,heterocycle, C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;provided that when R⁸ is heterocycle, attachment of R⁸ to V is through asubstitutable ring carbon; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, 2,2,2-trifluoroethyl,benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --N(R¹⁰)--, O or --C(═O)--; n is 0 or 1; mis 0, 1 or 2; and p is 0, 1, 2, 3 or 4, provided that p is not 0 if X isa bond or O; provided that A¹ (CR^(1a) ₂)_(n) is not a bond and providedthat (CR^(1b) ₂)_(p) --X is not a bond;or a pharmaceutically acceptablesalt thereof.
 6. The compound according to claim 4 of the formula F:##STR27## wherein: a is N or C;from 0-4 of b, c, d and e areindependently N, NH, O and S, and the remaining b, c, d and e atoms areindependently CH, provided that if a is C, then at least one of b, c, dor e is independently N, NH, O or S; R^(1a) is independently selectedfrom: hydrogen, C₃ -C₁ O cycloalkyl or C₁ -C₆ alkyl; R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or F, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, or--N(R¹⁰)₂ ; R² is selected from:a) hydrogen, b) unsubstituted orsubstituted aryl, unsubstituted or substituted heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹⁰C(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d) substituted C₁ -C₆ alkylwherein the substituent on the substituted C₁ -C₆ alkyl is selected fromunsubstituted or substituted aryl, unsubstituted or substitutedheterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹²O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, and R¹¹ OC(O)--NR¹⁰ --;provided that when R² is unsubstituted or substituted heterocycle,attachment of R² to the phenyl ring is through a substitutableheterocycle ring carbon; R³ is selected from H, halogen, CH₃ and CF_(3;)R^(6a), R^(6b), R^(6c) and R^(6d) are independently selected from:a)hydrogen, b) unsubstituted or substituted aryl, unsubstituted orsubstituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, NO₂, R¹⁰ C(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁ -C₆ alkyl, d)substituted C₁ -C₆ alkyl wherein the substituent on the substituted C₁-C₆ alkyl is selected from unsubstituted or 30 substituted aryl,unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; R^(9a) and R^(9b) are independently hydrogen,halogen, CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁-C₆ alkyl, 2,2,2-trifluoroethyl,benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; X is a bond, --CH═CH--,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, --N(R¹⁰)--, O or --(═O)--; m is 0, 1 or 2;and p is 0,1,2,3 or 4;or a pharmaceutically acceptable salt thereof. 7.The compound according to claim 5 of the formula G: ##STR28## wherein: ais N or C;from 0-4 of b, c, d and e are independently N, NH, O and S,and the remaining b, c, d and e atoms are independently CH, providedthat if a is C, then at least one of b, c, d or e is independently N,NH, O or S; R^(1a) is independently selected from: hydrogen, R¹⁰ O--,--N(R¹⁰)₂, F, C₃ -C₁₀ cycloalkyl or C₁ -C₆ alkyl; R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle or C₃ -C₁₀cycloalkyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;R² is selected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(o)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ --; provided that when R² is unsubstituted orsubstituted heterocycle, attachment of R² to the phenyl ring is througha substitutable heterocycle ring carbon; R³ is selected from H, halogen.CH₃ and CF₃ ; R^(6a), R^(6b), R^(6c) and R^(6d) are independentlyselected from:a) hydrogen, b) unsubstituted or substituted aryl,unsubstituted or substituted heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆alkenyl, C₂ -C₆ alkynyl, halogen, C₁ -C₆ perfluoroalkyl, R¹² O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, (R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN,NO₂, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) unsubstituted C₁-C₆ alkyl, d) substituted C₁ -C₆ alkyl wherein the substituent on thesubstituted C₁ -C₆ alkyl is selected from unsubstituted or substitutedaryl, unsubstituted or substituted heterocyclic, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹² O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,(R¹⁰)₂ NC(O)--, R¹⁰ ₂ N--C(NR¹⁰)--, CN, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, andR¹¹ OC(O)--NR¹⁰ ; R^(9a) and R^(9b) are independently hydrogen, halogen,CF₃ or methyl; R¹⁰ is independently selected from hydrogen, C₁ -C₆alkyl, 2,2,2-trifluoroethyl,benzyl and aryl; R¹¹ is independentlyselected from C₁ -C₆ alkyl and aryl; R¹² is independently selected fromhydrogen, C₁ -C₆ alkyl, C₁ -C₆ aralkyl, C₁ -C₆ substituted aralkyl, C₁-C₆ heteroaralkyl, C₁ -C₆ substituted heteroaralkyl, aryl, substitutedaryl, heteroaryl, substituted heteraryl, C₁ -C₆ perfluoroalkyl,2-aminoethyl and 2,2,2-trifluoroethyl; A¹ is selected from: a bond,--C(O)--, O, --N(R¹⁰)--, or S(O)_(m) ; m is 0, 1 or 2; and n is 0 or1;or the pharmaceutically acceptable salts thereof.
 8. A compound whichinhibits farnesyl-protein transferase which is: ##STR29## or apharmaceutically acceptable salt thereof.
 9. A compound which inhibitsfarnesyl-protein transferase which is: ##STR30## or a pharmaceuticallyacceptable salt thereof.
 10. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 1. 11. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 2. 12. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 3. 13. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 8. 14. A method for inhibiting farnesyl-proteintransferase which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 10. 15. Amethod for inhibiting farnesyl-protein transferase which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 11. 16. A method for inhibitingfarnesyl-protein transferase which comprises administering to a mammalin need thereof a therapeutically effective amount of a composition ofclaim
 12. 17. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 13. 18. A method for treatingcancer which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 10. 19. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 11. 20. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim
 12. 21. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 13. 22. A method for treatingneurofibromin benign proliferative disorder which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a composition of claim
 10. 23. A method for treating blindnessrelated to retinal vascularization which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 10. 24. A method for treating infections fromhepatitis delta and related viruses which comprises administering to amammal in need thereof a therapeutically effective amount of acomposition of claim
 10. 25. A method for preventing restenosis whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 10. 26. A method for treatingpolycystic kidney disease which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 10. 27. A pharmaceutical composition made by combining thecompound of claim 2 and a pharmaceutically acceptable carrier.
 28. Aprocess for making a pharmaceutical composition comprising combining acompound of claim 2 and a pharmaceutically acceptable carrier.